Dengue Virus Nonstructural Protein 1–Induced Antibodies Cross-React with Human Plasminogen and Enhance Its Activation

Chuang, Yung Chun; Lin, Jessica J.; Lin, Yee Shin; Wang, Shuying; Yeh, Trai Ming

doi:10.4049/jimmunol.1500057

Cited by 47 publications

(40 citation statements)

References 49 publications

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“…The NS1 protein of the DENV is a secretory lipoprotein that plays an essential role in viral replication intracellularly and causes many effects on the immune system in secretory forms . It is present intracellularly as a monomer, on the cell membrane as a dimer and as a hexamer with a lipid rich core in the secretory form .…”

Section: Introductionmentioning

confidence: 99%

Pathogenesis of vascular leak in dengue virus infection

2017

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SummaryEndothelial dysfunction leading to vascular leak is the hallmark of severe dengue. Vascular leak typically becomes clinically evident 3-6 days after the onset of illness, which is known as the critical phase. This critical phase follows the period of peak viraemia, and lasts for 24-48 hr and usually shows rapid and complete reversal, suggesting that it is likely to occur as a result of inflammatory mediators, rather than infection of the endothelium. Cytokines such as tumour necrosis factor-a, which are known to be elevated in the critical phase of dengue, are likely to be contributing factors. Dengue NS1, a soluble viral protein, has also been shown to disrupt the endothelial glycocalyx and thus contribute to vascular leak, although there appears to be a discordance between the timing of NS1 antigenaemia and occurrence of vascular leak. In addition, many inflammatory lipid mediators are elevated in acute dengue viral infection such as platelet activating factor (PAF) and leukotrienes. Furthermore, many other inflammatory mediators such as vascular endothelial growth factor and angiopoietin-2 have been shown to be elevated in patients with dengue haemorrhagic fever, exerting their action in part by inducing the activity of phospholipases, which have diverse inflammatory effects including generation of PAF. Platelets have also been shown to significantly contribute to endothelial dysfunction by production of interleukin-1b through activation of the NLRP3 inflammasome and also by inducing production of inflammatory cytokines by monocytes. Drugs that block down-stream immunological mediator pathways such as PAF may also be beneficial in the treatment of severe disease.

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Section: Introductionmentioning

confidence: 99%

Pathogenesis of vascular leak in dengue virus infection

2017

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“…Numerous studies illustrated that type I IFN is involved in the pathogenesis of DENV infection and the progression from undifferentiated febrile illness (DF) to life-threatening infection (DHF/DSS) (Jones et al, 2005;Ubol et al, 2008). Viral loads and the circulating levels of DENV NS1 antigen are the most important differences between DF and DHF in patients (Chuang et al, 2016;Halstead, 2015b). The high circulating levels of DENV NS1 antigen result in the enhancement of DENV infection via virus-antibody complexes.…”

Section: Discussionmentioning

confidence: 99%

Celastrol inhibits dengue virus replication via up-regulating type I interferon and downstream interferon-stimulated responses

Tseng

Lin

et al. 2017

Antiviral Research

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“…Primary antibodies included anti-NDH II (RHA), anti-E protein, anti-Lamin B (Santa Cruz Inc.), anti-prM protein (Abcam), anti-NS2B, anti-NS3, anti-NS4A, anti-NS4B, anti-NS5, anti-HA, anti-␤-actin (Sigma), anti-Calnexin, anti-FLAG (CST), and anti-glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (Proteintech). Anti-NS1 was a gift from Trai-Ming Yeh and Yung-Chun Chuang at National Cheng Kung University (42). Secondary antibodies included IRDye 800 CW-conjugated anti-rabbit IgG, IRDye 680 CW-conjugated anti-mouse IgG (LI-COR), horseradish peroxidase (HRP)-conjugated anti-mouse IgG (CST), and anti-rabbit IgG (Bio-Rad).…”

Section: Methodsmentioning

confidence: 99%

RNA Helicase A Is an Important Host Factor Involved in Dengue Virus Replication

Wang

Chen

Xie

et al. 2019

J Virol

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Dengue virus (DENV) utilizes host factors throughout its life cycle. In this study, we identified RNA helicase A (RHA), a member of the DEAD/H helicase family, as an important host factor of DENV. In response to DENV2 infection, nuclear RHA protein was partially redistributed into the cytoplasm. The short interfering RNA-mediated knockdown of RHA significantly reduced the amounts of infectious viral particles in various cells. The RHA knockdown reduced the multistep viral growth of DENV2 and Japanese encephalitis virus but not Zika virus. Further study showed that the absence of RHA resulted in a reduction of both viral RNA and protein levels, and the data obtained from the reporter replicon assay indicated that RHA does not directly promote viral protein synthesis. RHA bound to the DENV RNA and associated with three nonstructural proteins, including NS1, NS2B3, and NS4B. Further study showed that different domains of RHA mediated its interaction with these viral proteins. The expression of RHA or RHA-K417R mutant protein lacking ATPase/helicase activity in RHA-knockdown cells successfully restored DENV2 replication levels, suggesting that the helicase activity of RHA is dispensable for its proviral effect. Overall, our work reveals that RHA is an important factor of DENV and might serve as a target for antiviral agents. IMPORTANCE Dengue, caused by dengue virus, is a rapidly spreading disease, and currently there are no treatments available. Host factors involved in the viral replication of dengue virus are potential antiviral therapeutic targets. Although RHA has been shown to promote the multiplication of several viruses, such as HIV and adenovirus, its role in the flavivirus family, including dengue virus, Japanese encephalitis virus, and emerging Zika virus, remains elusive. The current study revealed that RHA relocalized into the cytoplasm upon DENV infection and associated with viral RNA and nonstructural proteins, implying that RHA was actively engaged in the viral life cycle. We further provide evidence that RHA promoted the viral yields of DENV2 independent of its helicase activity. These findings demonstrated that RHA is a new host factor required for DENV replication and might serve as a target for antiviral drugs.

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Dengue Virus Nonstructural Protein 1–Induced Antibodies Cross-React with Human Plasminogen and Enhance Its Activation

Cited by 47 publications

References 49 publications

Pathogenesis of vascular leak in dengue virus infection

Pathogenesis of vascular leak in dengue virus infection

Celastrol inhibits dengue virus replication via up-regulating type I interferon and downstream interferon-stimulated responses

RNA Helicase A Is an Important Host Factor Involved in Dengue Virus Replication

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